The invention concerns an implant material based on a polymer system of at least two components and its use as a bone cement, bone adhesive, bone replacement material or active ingredient carrier.
Polymer-based bone cements are clinically used primarily for attachment of joint implants. They have been established for approximately 50 years in clinical practice and today are used worldwide in approximately 5 million cases. The chemical composition of the bone cements has practically remained unchanged during this time. It is comprised substantially of a powder component that contains one or several polymers, primarily comprised of acrylates, methacrylates, and styrene, or copolymers of these monomers or mixtures of the corresponding homopolymers and/or copolymers (referred to summarily as PMMA). Further components of the powder component are in general an x-ray contrast agent and a radical starter. As an x-ray contrast agent preferably barium sulfate or zirconium dioxide are used. As a radical starter in all commercially available bone cements dibenzoyl peroxide (BPO) is used. The second bone cement component is a reactive organic liquid that is quite predominantly comprised of the monomer methyl acrylate (MMA) and, in rare cases, also contains other esters of acrylic acid or methacrylic acid. Further components are a co-starter (also referred to as activator or co-initiator) and a stabilizer or inhibitor. As a co-starter in almost all commercial bone cements dimethyl-p-toluidine (DMPT) is used, very rarely another tertiary amine. As inhibitor primarily hydroquinone or one of its derivatives is employed.
In addition, bone cements can also contain further substances (antibiotics, coloring agents) that in the present context will however initially not be considered.
When in a conventional bone cement powder and liquid are mixed with one another, the initiator (BPO) and co-starter (DMPT) react with one another under formation of radicals that, in turn, attack the double bonds of the monomer molecules and trigger a polymerization (chain) reaction until the predominant portion of the monomer has reacted to polymer chains. Parallel to this, the monomer solubilizes or dissolves a portion of the polymer which initially may lead to a fast increase of viscosity of the cement material and which causes an intimate connection of powder and polymerizing liquid. The complete curing reaction from the mixture to the full loading capacity is completed in conventional PMMA bone cement in approximately 10-30 minutes. PMMA bone cements, despite the long experience and the wide use, have a series of disadvantages:                Mixing: the cement powder is a mixture of very fine powders that, in turn, have very different properties (particle size, density differences of 1.18 for PMMA and 5.85 for ZrO2) and therefore are difficult to be homogeneously mixed and therefore require corresponding manufacturing expenditure. Mixing of the cement powder with the monomer liquid also constitutes a problem because the viscosity of the liquid increases very quickly and then a homogenous mixing is made difficult. A substantially pore-free cement material is practically achieved only by using complex and expensive mixing systems.        Shrinkage: during the polymerization reaction the density upon passing from pure monomer to polymer increases by more than 20% and the volume decreases correspondingly. Since the bone cement largely contains already polymerized material (PMMA proportion), in this system the shrinkage is significantly lower and is indicated to be approximately 2-5% (Kühn, Bone Cements, Springer Verlag, 2000, ISBN 3-540-67207-9). Aside from the high polymerization heat, the shrinkage can be considered a significant clinically relevant disadvantage of conventional bone cements that limits the application possibilities with respect to important clinical indications. In case of required great layer thicknesses (as, for example, when replacing a prosthesis) the shrinkage can cause the formation of a distinct gap between cement and bone so that a physiological force transmission is no longer possible.        Polymerization heat: the polymerization reaction of MMA to PMMA is greatly exothermic. The obtained peak temperatures according to ISO 5833 are at approximately 80° C. and depend quite considerably on the quantity ratio of monomer to total cement weight and to a lesser degree on the polymerization kinetics. Clinically relevant is the high polymerization heat in particular for large quantities of cement to be applied when the surrounding tissue cannot remove fast enough the generated heat in order to avoid tissue necrosis.        Mechanics: for most of the applications customary today PMMA bone cement has satisfactory mechanical properties. For some new applications—in particular, vertebroplastics or generally stiffening of spongy bone—the high stiffness is however often considered a disadvantage. A reduced stiffness may provide clinical advantages in many fields of application, even the traditional ones.        Active ingredient release: the majority of bone cement applications is focused today in many countries on the antibiotics-containing versions for prophylaxis of foreign body-associated infections. In order to achieve satisfactory release, very high doses must be mixed into the cement of which the predominant part is released over a very long period of time in very low concentrations (or not at all). This fact is often linked with the development and spread of resistant bacteria strains. Obtaining satisfactory effective levels at much lower dosages that may be released completely over a shorter period of time is therefore desirable.        Tissue compatibility: PMMA is tissue-compatible to a satisfactory extent and fulfills the standardized requirements with respect to biocompatibility of implant materials. PMMA however is not integrated into the bone but is encapsulated by scar tissue. This has biochemical causes as well as structural reasons. Solid bone cement provides to the surrounding bone no possibility to grow into an external pore system and to thus achieve a secondary interlocking as is the case in modern uncemented permanent metal implants.        
WO 2005/009481 A1 discloses a bone cement containing a surface-active agent and comprised of a liquid component and a solid component. The powder component is unchanged relative to conventional bone cement; only the liquid component contains in addition to the monomer a surface-active ingredient and an accelerator. Immediately before use the components are mixed. The goal of WO 2005/009481 A1 is to impart to a conventional bone cement an improved release of antibiotic agents.
WO 2004/071543 A1 discloses an injectable bone replacement mixture of a) a two-component powder liquid bone cement, b) a further component that is not miscible with the cement paste, and c) an x-ray contrast agent. After mixing the components a self-curing porous bone replacement material is said to be formed in which component b after curing can be washed out. The teaching of WO 2004/071543 A1 is limited to a conventional powder liquid system to which, only after mixing the conventional components has been done, an immiscible liquid for pore formation is added.
DE 32 45 956 A1 concerns a surgical material on the basis of liquid monomer and powdery polymer acrylic acid esters and/or methacrylic acid esters, catalysts, accelerators, and optionally additives, in which the liquid component is not an aqueous emulsion but a solution with special organic liquids that do not participate in the polymerization reaction and that lead to a reduced heat development upon mixture and incorporation of the surgical material.
U.S. Pat. No. 4,093,576 discloses a bone cement mixture of a polymer powder and a highly viscous water-soluble gel of more than 200,000 centipoise that is compatible therewith. Upon mixing these components a porous bone replacement material is produced.
The object of DE 10 2004 049 A1 is an antibiotic-containing or antibiotics-containing PMMA bone cement with a powder component and a liquid component. In this connection, as a result of the specific composition of the added antibiotics their release is said to be significantly increased.
Cement-type compositions that are comprised of two pastes and are offered in double chamber syringes and are combined and reacted by means of static mixers have been known primarily from dental practice for quite some time. A product derived therefrom (Cortoss of the Orthovita company) has been developed in recent years also for the field of orthopedics. The dental filling materials as well as the product Cortoss differ significantly from the conventional bone cements as a result of their proportion of glass-ceramic filler materials in the first paste. As a starter system BPO/DMPT is employed wherein DMPT is contained in the first paste and BPO is present in dissolved form in the second paste and is stable with regard to storage only by cooling. A satisfactory storage stability is ensured for this product only for continuous cooling and the mineral fillers that are added in high concentration have the tendency, despite the high viscosities, to form sediments. The implant material according to the present invention is significantly distinguished from the products such as Cortoss and dental filling materials in that the materials according to the present invention always contain a suspension of polymer powders in carrier liquids in which they are neither soluble nor swellable to a significant extent. Furthermore, there is a significant material differentiation in that the products such as Cortoss in both cement components contain as monomers primarily macromers with more than one double bond while the monomer liquid in the materials according to the present invention predominantly are comprised of the monovalent MMA and polymers dissolved therein.
In recent years publications in regard to two-paste PMMA cements have also been published in scientific literature which are based on conventional bone cements (Li et al., Bioactive and osteoporotic bone cement, U.S. Pat. No. 6,593,394 B1: Gilbert J L, Hasenwinkel J M, Wixson R L, Lautenschlager E P, J. Biomed, Mater. Res. 2000 October 52(1):210-218). These cases concern exclusively highly viscous solutions of PMMA copolymers in MMA with high contents of mineral filler materials in which one paste contains the BPO and the other one the DMPT. These compositions have thus the same technological disadvantages as Cortoss with regard to storage stability and sedimentation. Also disadvantageous in this connection is the very high heat development during polymerization that is caused by the necessary high MMA contents for the paste preparation.
In the early '80s of the 20th century the company Beiersdorf developed a bone cement and introduced it into the market which bone cement contains in the powder component a conventional composition but as a monomer liquid contains an emulsion of approximately 10% water in MMA. The goal was primarily lowering of the polymerization temperature. With the exception of use of emulsifying agents and aqueous components in the overall formulation there are no principal commonalities with the composition according to the present invention.
Inspired by clinical problems in connection with demands on bone cements for vertebroplastics, in recent years a series of tests for blending bone cements with aqueous polymer solutions, in particular hyaluronic acid, have been performed in order to reduce the stiffness of the cements.
According to Boger A., Verrier S., Bohner M., Heini P., Schneider E.—Injizierbarer poröser Knochenzement für die Vertebroplastik mit physiologisch angepassten mechanischen Eigenschaften (Injectable porous bone cement for vertebroplastics with physiologically matched mechanical properties), Bern; DGU, 2005—conventional bone cements were first mixed and subsequently hyaluronic acid was admixed. This procedure leads in contrast to the method according to the invention to results that are hardly reproducible and causes dramatic strength losses already for relatively low quantities of hyaluronic acid. The fundamental reason for the unsatisfactory results is linked to the practically unachievable uniform dispersion of aqueous solutions in an already premixed bone cement paste under conditions in the operating room and with means that are available therein. The obtained cement materials are correspondingly inhomogeneous so that this method is impractical for clinical use. The cited works are therefore in no way an anticipation of the actual invention since neither the concrete teaching is disclosed nor the obtained results are achieved.
As a whole, the aforementioned works shows that there is an acute interest in an improvement of conventional bone cements and that the solutions that have been presented in the past are still far removed from a satisfactory solution.
The present invention ties in with the weak points of conventional PMMA bone cements in that it follows a new approach for preparation and material composition of bone cements while it is still based on the established starting materials. In this way, implant materials, in particular for bone cements, for vertebroplastics and filling of bone defects in the context of prosthesis revision and for the augmentation of osteoporotic bones are to be provided but also materials for non-medical fields of applications are to be developed.